Penicillin composition for pericardial introduction



i' 1' I I ite States This invention relates to medicinal compositions adapted for pericardial introduction. More particularly, the invention relates to compositions comprising procaine penicillin, which provide unexpected, beneficial results following pericardial introduction into patients who have undergone a coronary accident or 'who are suifering from certain types of heart disease in which one of the symptoms is pronounced local coronary pain associated with circulatory impairment or coronary occlusion. Clinically, this pain is a most distressing phenomenon that lasts day and night for several days. It not only is of great concern to the physician because of the possibility of sec ondary spasms occurring, but also is amost fatiguing and panicking symptom to the patient himself.

Heretofore, procaine penicillin in crystalline form has been available for intramuscular injection by means of a syringe and hollow needle particularly in those cases where a repository antibiotic effect is desired. The conventional forms of procaine penicillin, however, are not suited and in fact are not intended for the treatment of the type of heart disease which is relieved by the compositions of the invention.

According to the invention, there are provided compositions in dosage form for pericardial introduction containing procaine penicillin preferably in suspended form in a flowable vehicle. The procaine penicillin contained in the compositions of the invention is characterized by a relatively large average crystal size. Each dosage unit thereof contains a sufiicient quantity of large crystals to afford on administration continous abrasion and stimulation of the pericardial tissue, i.e., the tissue interphase between the heart muscle proper and the pericardium. For this purpose each dosage unit contains, in accordance with the invention, approximately 2 to 10, and preferably 4 to 8 grams of procaine penicillin crystals exceeding 420 microns in length. The crystals may be as large as about 940 microns in length (i'.e., No. 16 mesh size) or larger, but for practical purposes the upper limit of crystal size is such that when suspended in a vehicle the crystals can 'be administered by means of a syringe or equivalent fluid pumping device without undue blockage of the orifice or chamber. Conveniently, the compositions of the invention contain procaine penicillin crystals ranging in size from about 420 microns to over 860 microns but less than 920 microns. A preferred composition contains per unit dosage about 3-3.2 g. of crystals ranging in length between 420-860 microns and 2.6-2.8 g. of

larger crystals ranging upward to 920 microns. In contrast to the crystal sizes of procaine penicillin of the instant invention, the conventional forms of procaine penicillin used for intramuscular injection seldom if ever exceed 100 microns.

The large procaine penicillin crystals employed in the compositions of the invention are conveniently prepared by combining separate aqueous methanolic solutions of equimolar amounts of procaine and a penicillin salt and allowing the resulting solution to stand for a sufficient length of tune to permit the growth of a crystalline precipitate. The precipitate is then recovered, dried and, if desired, classified according to size.

The term flowable vehicle as used herein refers not only to substances which are normally liquid and flow at atent O room temperature, but also substances which are solid at room temperature but which, when warmed to higher temperature up to body temperature, have the fluid properties of a liquid or semi-solid. A wide variety of flowable vehicles are suitable for the invention, the main requirement being that such vehicles be compatible With, and non-injurious to, the pericardial tissue while at the same time being sterilizable and compatible with procaine penicillin. Water is eminently suited for this purpose as well as aqueous isotonic solutions. Water-in-oil and oilin-water emulsions are also suitable. Examples of such vehicles are natural butters such as dairy butter and cocoa butter; gelatin, agar and acacia solutions, polyviuylpyrrolid'one solutions; and the like. Optionally, the compositions of the invention may contain one or more agents to enhance stability, fluidity, etc., and other agents such as isotonic agents, coloring agents, etc. For example, the

compositions may contain a fluid-izing agent such as mannitol, sorbitol, sucrose and the like which advantageously may provide isotonicity. For the purposes of the invention each dosage unit comprises a suflicient volume of vehicle to hold and suspend the procaine penicillin crystals and other ingredients present, and to provide the bulk necessary to substantially engross the pericardial cavity upon administration of the total dosage. In the case of water, for example, a convenient volume is 20 ml.

In addition to the large procaine penicillin crystals mentioned above, a preferred embodiment of the invention \also includes procaine penicillin in micronized (the term micronized as used herein refers to crystals of small size 90% of which are less than 10 microns in largest dimension) form in an amount suflicient to maintain the above-mentioned large crystals in a state of fluidity when suspended in a vehicle, preferably from 10 to 20 grams per unit dosage. The micronized procaine penicillin serves conveniently as a carrier for the large procaine penicillin crystals and additionally protects the large crystals against the solvent action of the vehicle and thereby maintains the large crystals in substantially their original condition over relatively long' periods of time.

. For enhanced stimulant laction, compositions of the invention may also contain an inert abrasive such as finely divided asbestos powder.

The invention also contemplates dosage forms in which the procaine penicillin is present in dry, crystalline form if desired together with micronized procaine penicillin,

fiuidizing agents, etc., to which, just prior to administration, is added the desired liquid vehicle such as water, whereupon the resulting mixture is agitated to provide a suspension of the procaine penicillin crystals, suitable for direct administration into the pericardium. Such dosage forms are advantageous in that during storage they have a relatively long shelf-life and for purposes of administration the fluidity thereof can be adjusted and controlled by the clinician not only by selecting any desired vehicle, but also by varying the amount of vehicle to provide the particular degree of fluidity required. A preferred dosage form, in accordance with the invention, is a sealed receptacle of suitable volume, such as a syringe or chamber insertable in a syringe, containing a unit dose, i.e.,

; 2 about 2 to 10 grams, and prefer-ably 4 to 8 grams, of dry procaine penicillin crystals to which can be added just prior to use the desired vehicle for pericardial introduction. The procaine penicillin content of such a preferred dosage form, in the amounts mentioned, is in the form of crystals exceeding 420 microns in length. The dosage may also include smaller crystals and preferably includes approximately 10-20 g. of micronized procaine penicillin.

The compositions of the invention should be rendered sterile before use and preferably the ingredients, prior to and during formulation, should be prepared and bandled under aseptic conditions. Sterilization is accomplished by conventional means such as heating, exposure to ethylene oxide gas, etc.

The compositions of the invention are administered under sterile conditions by recognized medical techniques into the pericardial chamber through a surgical incision. In this connection, it is known that heart muscle under duress does not, in many cases, mobilize pericardial fluid as it should. Part of the loss of efficiency of the pericardium is due to the insulation generated by the accumulated fluid which does not allow the pericardium to exert uniform pressure about the more vital muscles of the heart. Therefore, immediately prior to the administration of the instant compositions, it is desirable to remove any accumulation of fluid from the pericardial chamber. Removal of the fluid in this manner serves to facilitate the introduction of the desired procaine penicillin dosage. Such introduction is carried out conveniently by means of any suitable pumping device such as a syringe containing the composition, to the orifice of which is attached a catheter or tube having inside dimensions suificiently large (e.g. 3 to mm. or larger in diameter) to permit the flow of the composition, the catheter being inserted through the incision directly into the pericardium. Administration is accomplished readily by causing the composition to how, if necessary after preliminary warming of the composition to give it greater fluidity, into the pericardial chamber, following which the injected material becomes uniformly distributed as the result of local intrapericardi-al motion. Following instillation, the dosage is allowed to remain indefinitely in the pericardium where it provides a continuing local stimulant and abrasive action. Such action favors the establishment of collateral blood circulation to any areas of the heart muscle where the circulation may be inadequate, thereby combatting anoxia or tissue asphyxiation. In addition to the desired stimulant and abrasive action, the compositions of the invention provide a repository antibacterial eifeot and further importantly provide essentially complete and sustained alleviation of local pain within a short period following instillation. Ordinarily, a single dosage provides subjective relief from pain for several days, i.e. 3 to 4 days, so that further therapy is unnecessary, at least until any later occurrence of another coronary episode.

The following description, exemplary of a preferred embodiment of the invention, illustrates in detail a procedure used for the preparation of procaine penicillin crystals and the formulation thereof into a composition suitable for pericardial introduction.

PREPARATION OF PROCAINE PENICILLIN CRYSTALS Lot A Dilute methanol was prepared by dissolving 3598 ml. of methanol in suflicien-t water to make 5140 of solution.

436 gm. (1.6 moles) of procaine hydrochloride was dissolved in 1300 of dilute methanol and filtered with suction (medium sintered glass funnel) rinsing with 420 ml. of the solvent.

A solution of 596 gm. (1.6 moles) of potassium penicillin in 17 20 ml. of dilute methanol was prepared exactly as the procaine solution.

1700 ml. of dilute methanol was filtered (suction, medium sintered glass funnel).

The solutions were transferred to a 22 1. wide mouth, round bottom flask (free of scratches), rinsing each container with 350 ml. of the filtered methanol solution. The resulting clear solution was mixed by swirling. After standing a few minutes a crystal of procaine penicillin was added.

The flask was stoppered and the reaction mixture allowed to stand undisturbed for 88 hours at room temperature.

The resulting crystalline procaine penicillin was collected with suction on a medium sintered glass funnel and washed with two 500 ml. portions of the filtered solvent. After drying to constant weight (in vacuo, room temperature) 489 gm. of product, M.P. 127-9 0, was obtained.

The clusters of large crystals were broken up with a mortar and pestle and pressed through a #16 screen.

Lot B Dilute methanol was prepared by dissolving 16,540 ml. of methanol in sufiicient distilled 'water to make 23.5 1. of solution.

2120 gm. (7.77 moles) of procaine hydrochloride was dissolved in 7 l. of the dilute methanol and filtered with suction (medium sintered glass funnel), rinsing with 1500 ml. of the solvent.

A solution of 2896 gm. (7.77 moles) of potassium penicillin in 8.5 l. of the dilute methanol was prepared exactly as the procaine solution.

The penicillin solution was still slightly hazy. It was clarified by filtering with suction through a Alsop pad, rinsing with about 1 l. of the solvent.

5.5 l. of the dilute methanol was filtered (suction, med. sintered glass funnel).

The solutions were transferred to a new 10 gal. round bottom, open top glass tank, rinsing each container with 1 l. of the filtered solvent.

The resulting solution was mixed thoroughly with a stirring rod. A few crystals had formed in the solution after it stood a few minutes. The tank was sealed and allowed to stand undisturbed at room temperature.

After standing 64 hrs. the crystalline product was collected with suction on a medium sintered glass funnel and Washed with two 1750 ml. portions of the filtered methanol solution.

After drying to constant weight (in vacuo, room tem perature), 2247 gm. of the product, M.P. 1279 C., was obtained.

The clusters of very large crystals were broken up by passing through a hand mill and finally pressed through a #16 screen.

Lots A and B were blended in a PK blender for about 40 minutes.

The blended product had the following particle-size distribution:

Percent (by weight)- Dimension (microns) 0 Greater than 940. 33.7 Above 860, to 940. 37.4 Above 420, to 860. 13.2 Above 250, to 420. 4.8 Above 177, to 250. 1.9 Above 149, to 177. 7.7 Less than 149.

PREPARATION OF STERILE COMPOSITION FOR PERICARDIAL INTRODUCTION (A) Procaine penicillin G, micronized sterile Precautions: Mix the solution and powders and fill tubes under aseptic conditions. Keep the suspension well mixed during the filling procedure.

(1) Screen the asbestos through a #16 screen then through a #30 screen.

(2) Autoclave the screened asbestos for 30 minutes.

Place overnight in an oven at C. to dry.

(3) Mix the dried asbestos and the procaine penicillins in a 10 liter bottle. Ster-ilize with ethylene oxide.

Analysis, by weight, per tube: Percent Procaine penicillin G micronized 35.32 Procaine penicillin 17.66 Asbestos 0.66 D-sorbitol 2.21 Water 44.15

An alternative preparation, in dry form for subsequent reconstitution with an aqueous vehicle, is obtained by blending the above dry ingredients A, B and C with 100 g. of D-sorbitol powder and filling the mixture in 25-gram amounts into sterile, glass syringe tubes.

What is claimed is:

1. A procaine penicillin composition in dosage form for pericardial introduction which comprises a suspension in a flowable vehicle of procaine penicillin crystals, each dosage unit of said composition containing approximately 2 to grams of procaine penicillin crystals exceeding 420 microns in length.

2. A composition according to claim 1 in which the fiowable vehicle contains water.

3. A composition according to claim 1 containing approximately 10 to grams of micronized procaine penicillin per unit dosage.

4. A composition according to claim 1 containing er unit dosage about 3 to 3.2 grams of procaine penicillin crystals ranging in length between 420 to 860 microns and about 2.6 to 2.8 grams of larger procaine penicillin crystals ranging in length upward to 920 microns.

5. A composition according to claim 1 in which the flowable vehicle is fluid at body temperature.

6. A procaine penicillin dosage unit form adapted for formulation with a vehicle, which comprises a sealed receptacle containing approximately 2 to 10 grams of procaine penicillin crystals exceeding 420 microns in length, the contents of said receptacle being adapted for pericardial introduction.

7. A procaine penicillin dosage unit form in accordance with claim 6 in which the receptacle also contains approximately 10 to 20 grams of micronized procaine penicillin crystals.

8. A procaine penicillin dosage unit form adapted for formulation with a vehicle, which comprises a sealed receptacle containing about 3 to 3.2 grams of procaine penicillin crystals ranging in length between 420 to 860 microns, about 2.6 to 2.8 grams of larger crystal-s ranging in length upward to 920 microns, and about 10 to '20 grams of micronized procaine penicillin, the contents of said receptacle being adapted for pericardial introduction.

Buckwalter May 9, 1950 Kirchmeyer Apr. 10, 1956 

1. A PROCAINE PENCILLIN COMPOSITION IN DOSAGE FORM FOR PERICARDIAL INTRODUCTION WHICH COMPRISES A SUSPENSION IN A FLOWABLE VEHICLE OF PROCAINE PENCILLIN CRYSTALS, EACH DOSAGE UNIT OF SAID COMPOSITION CONTAINING APPROXIMATELY 2 TO 10 GRAMS OF PROCAINE PENCILLIN CRYSTALS EXCEEDING 420 MICRONS IN LENGTH. 